Human Skin Diseases Research Articles

Cannabinol modulates the endocannabinoid system and shows TRPV1-mediated anti-inflammatory properties in human keratinocytes.

Cannabinol (CBN) is a secondary metabolite of cannabis whose beneficial activity on inflammatory diseases of human skin has attracted increasing attention. Here, we sought to investigate the possible modulation by CBN of the major elements of the endocannabinoid system (ECS), in both normal and lipopolysaccharide-inflamed human keratinocytes (HaCaT cells). CBN was found to increase the expression of cannabinoid receptor 1 (CB1) at gene level and that of vanilloid receptor 1 (TRPV1) at protein level, as well as their functional activity. In addition, CBN modulated the metabolism of anandamide (AEA) and 2-arachidonoylglicerol (2-AG), by increasing the activities of N-acyl phosphatidylethanolamines-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH)-the biosynthetic and degradative enzyme of AEA-and that of monoacylglycerol lipase (MAGL), the hydrolytic enzyme of 2-AG. CBN also affected keratinocyte inflammation by reducing the release of pro-inflammatory interleukin (IL)-8, IL-12, and IL-31 and increasing the release of anti-inflammatory IL-10. Of note, the release of IL-31 was mediated by TRPV1. Finally, the mitogen-activated protein kinases (MAPK) signaling pathway was investigated in inflamed keratinocytes, demonstrating a specific modulation of glycogen synthase kinase 3β (GSK3β) upon treatment with CBN, in the presence or not of distinct ECS-directed drugs. Overall, these results demonstrate that CBN modulates distinct ECS elements and exerts anti-inflammatory effects-remarkably via TRPV1-in human keratinocytes, thus holding potential for both therapeutic and cosmetic purposes.

Therapeutic efficacy of cold atmospheric plasma in four golden retrievers with acute otitis externa.

Cold atmospheric plasma (CAP) is a new therapeutic tool used to treat various skin diseases in humans and animals. To evaluate the effect of CAP in the treatment of canine acute otitis externa (AOE). Four client-owned golden retriever dogs with bilateral AOE. After cleaning with a commercial ear cleanser, right ears (STANDARD group) were treated with an antibiotic/antifungal/corticosteroid combination and left ears (CAP group) were treated with CAP every three days for a total of four treatments. Cytological score and otitis index score (OTIS)3 were recorded for each ear on Day (D)0, D10 and D15. At D10 and D15, owners and investigators recorded an overall assessment. In both groups, OTIS3 and cytological score decreased over the study period. The overall assessment scale ranged from moderate to excellent in both groups. Cold atmospheric plasma treatment showed equal therapeutic effect compared with a commercial topical anti-inflammatory and antimicrobial ear treatment.

A Review of the Benefits of the Sustainable Utilization of Shrimp Waste to Produce Novel Foods and the Impact on Human Health

In recent years, there has been an increase in the industrial processing of shrimp, aiming to cover the increasing demand for shrimp products for human consumption, and, consequently, an increase in shrimp by-products as shrimp waste. This waste includes the cephalothoraxes, heads, shells, tails, pleopods, and exoskeleton appendages of processed shrimps. The appropriate method for the enzymatic hydrolysis of shrimp waste can recover its bioactive substances, including carotenoids. Thus, these xanthophylls and carotenes are of high financial interest and have high antioxidant, anti-inflammatory, and anti-cancer activities. Therefore, these substances can be incorporated into fish feed as ingredients that improve fish health and simultaneously lead to the production of aquaculture fishes similar in coloration to the wild ones. Thus, the consumption of such novel food acts as a preventive factor for human health. In this regard, β-carotene has antioxidant and fat-soluble activities owing to vitamin A sufficiency and has an anti-cancer effect, too. Canthaxanthin can be used as a product for personal care and as a natural tanning agent for human skin. Zeaxanthin and lutein have positive effects on various eye and heart diseases, neuronal damage, human skin diseases, and certain types of cancer. Astaxanthin also has anti-diabetic and anti-obesity properties. Therefore, the purpose of this review is to highlight the sustainable utilization of shrimp waste via enzymatic hydrolysis, the benefits of a fish diet enriched with astaxanthin, the consumption of fish enriched with carotenoids, and the effects of carotenoids on human health. The problem of shrimp waste disposal affects the environment, does not contribute to sustainable development, and is directly related to the phenomenon of environmental change.

TGFβ-mediated inhibition of hypodermal adipocyte progenitor differentiation promotes wound-induced skin fibrosis.

Aberrant activation of dermal fibroblasts during wound healing often leads to debilitating fibrotic changes in the skin, such as scleroderma and keloids. However, the underlying cellular and molecular mechanisms remain elusive. Here, we established a wound-induced skin fibrosis (WISF) mouse model in mature adult mice, characterised by excessive deposition of collagen bundles, loss of dermal adipocytes, and enrichment of DPP4+Ly6A+THY1+ hypodermal interstitial adipocyte progenitors (HI-APs) and pericytes, resembling human fibrotic skin diseases. This WISF model exhibited an age-dependent gain of fibrotic characteristics, contrasting with the wound-induced hair neogenesis observed in younger mice. Through comprehensive analyses of the WISF, we delineated a trajectory of fibroblast differentiation that originates from HI-APs. These progenitors highly expressed several extracellular matrix (ECM) genes and exhibited a TGFβ pathway signature. TGFβ was identified as the key signal to inhibit the adipogenic potential and maintain the fibrogenic potential of dermal APs. Additionally, administering a TGFβ receptor inhibitor to wound scar reduced the abundance of ECM-producing APs. Finally, analysis of human scleroderma skin tissues revealed a negative correlation between the expression of AP-, ECM-, and TGFβ pathway-related genes and PPARG. Overall, this study establishes a wound-induced skin fibrosis mouse model and demonstrates that TGFβ-mediated blockage of HI-AP differentiation is crucial for driving fibrotic pathology. Targeting HI-APs and adipogenesis may provide novel avenues for developing disease-modifying therapies for fibrotic skin diseases.

Effect of Using GLCM and LBP+HOG Feature Extraction on SVM Method in Classification of Human Skin Disease Type

Skin diseases have been ranked third out of ten diseases suffered by outpatients in many hospitals in Indonesia. The public often underestimates these diseases because they are considered not to cause death. In general, dermatologists diagnose skin diseases using the biopsy process, but the biopsy process is quite expensive and can cause injury to the skin. Each skin disease has different texture and shape characteristics, so classification can be used to distinguish the type of skin disease. This study compares LBP+HOG and GLCM feature extraction with the SVM classification method to determine the best feature extraction in skin disease classification. This research compares GLCM and LBP+HOG feature extraction using the SVM method. GLCM is used to measure the relationship between pixel intensities in the image, while LBP+HOG combines information about the texture and shape of the image. The test results show that the GLCM feature extraction method with SVM classification achieves an accuracy of 74%. In this test, the parameters C=100 and the features used are homogeneity, contrast, energy, correlation, ASM, and dissimilarity. Meanwhile, extraction with LBP+HOG resulted in an accuracy of 68%.

Card9 and MyD88 differentially regulate Th17 immunity to the commensal yeast Malassezia in the murine skin.

The fungal community of the skin microbiome is dominated by a single genus, Malassezia. Besides its symbiotic lifestyle at the host interface, this commensal yeast has also been associated with diverse inflammatory skin diseases in humans and pet animals. Stable colonization is maintained by antifungal type 17 immunity. The mechanisms driving Th17 responses to Malassezia remain, however, unclear. Here, we show that the C-type lectin receptors Mincle, Dectin-1, and Dectin-2 recognize conserved patterns in the cell wall of Malassezia and induce dendritic cell activation in vitro, while only Dectin-2 is required for Th17 activation during experimental skin colonization in vivo. In contrast, Toll-like receptor recognition was redundant in this context. Instead, inflammatory IL-1 family cytokines signaling via MyD88 were also implicated in Th17 activation in a T cell-intrinsic manner. Taken together, we characterized the pathways contributing to protective immunity against the most abundant member of the skin mycobiome. This knowledge contributes to the understanding of barrier immunity and its regulation by commensals and is relevant considering how aberrant immune responses are associated with severe skin pathologies.

Medicinal Plants Recommendation System using ROC and MOORA

Kalimantan has extraordinary biodiversity, including medicinal plants. Medicinal plants are a type of plant that certain parts, such as roots, leaves, bark, stems, and the results of their excretions. However, people sometimes need help choosing plants that suit their needs because of the many types of medicinal plants and the need for knowledge regarding their use. Decision support systems (DSS) combine computer capabilities with data processing or manipulation that utilizes unstructured models or solution rules. Furthermore, the method of documenting knowledge of traditional medicine is through the media of information systems. This system helps select medicinal plants according to user needs. This research developed a DSS using Rank Order Centroid (ROC) and Multi-Objective Optimization by Ratio Analysis (MOORA) methods to select medicinal plants for fungal and skin infections, including Furuncles, Tinea corporis, Tinea versicolor, and Acne. ROC method for determining criteria weight values. This research has four criteria: plant part, processing method, use method, and habitus. Determining recommendations for alternative ranking results using the MOORA method. This study aims to help the public get recommendations for medicinal plants in human skin disease treatment. This study aims to increase the preservation of biodiversity, particularly sustainable medicinal plants in the tropical rainforest of East Kalimantan.

Increasing GSH-Px Activity and Activating Wnt Pathway Promote Fine Wool Growth in FGF5-Edited Sheep.

Fibroblast growth factor 5 (FGF5) plays key roles in promoting the transition from the anagen to catagen during the hair follicle cycle. The sheep serves as an excellent model for studying hair growth and is frequently utilized in various research processes related to human skin diseases. We used the CRISPR/Cas9 system to generate four FGF5-edited Dorper sheep and only low levels of FGF5 were detected in the edited sheep. The density of fine wool in GE sheep was markedly increased, and the proportion of fine wool with a diameter of 14.4-20.0 μm was significantly higher. The proliferation signal in the skin of gene-edited (GE) sheep was stronger than in wild-type (WT) sheep. FGF5 editing decreased cortisol concentration in the skin, further activated the activity of antioxidant enzymes such as Glutathione peroxidase (GSH-Px), and regulated the expression of Wnt signaling pathways containing Wnt agonists (Rspondins, Rspos) and antagonists (Notum) in hair regeneration. We suggest that FGF5 not only mediates the activation of antioxidant pathways by cortisol, which constitutes a highly coordinated microenvironment in hair follicle cells, but also influences key signals of the Wnt pathway to regulate secondary hair follicle (SHF) development. Overall, our findings here demonstrate that FGF5 plays a significant role in regulating SHF growth in sheep and potentially serves as a molecular marker of fine wool growth in sheep breeding.

FBP1 orchestrates keratinocyte proliferation/differentiation and suppresses psoriasis through metabolic control of histone acetylation

Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.

From GWASs toward Mechanistic Understanding with Case Studies in Dermatogenetics

Many human skin diseases result from the complex interplay of genetic and environmental mechanisms that are largely unknown. GWASs have yielded insight into the genetic aspect of complex disease by highlighting regions of the genome or specific genetic variants associated with disease. Leveraging this information to identify causal genes and cell types will provide insight into fundamental biology, inform diagnostics, and aid drug discovery. However, the etiological mechanisms from genetic variant to disease are still unestablished in most cases. There now exists an unprecedented wealth of data and computational methods for variant interpretation in a functional context. It can be challenging to decide where to start owing to a lack of consensus on the best way to identify causal genetic mechanisms. This article highlights 3 key aspects of genetic variant interpretation: prioritizing causal genes, cell types, and pathways. We provide a practical overview of the main methods and datasets, giving examples from recent atopic dermatitis studies to provide a blueprint for variant interpretation. A collection of resources, including brief description and links to the packages and web tools, is provided for researchers looking to start in silico follow-up genetic analysis of associated genetic variants.

Unveiling the Role of Endoplasmic Reticulum Stress Pathways in Canine Demodicosis.

Canine demodicosis is a prevalent skin disease caused by overpopulation of a commensal species of Demodex mite, yet its precise cause remains unknown. Research suggests that T-cell exhaustion, increased immunosuppressive cytokines, induction of regulatory T cells and increased expression of immune checkpoint inhibitors may contribute to its pathogenesis. This study aimed to gain a deeper understanding of the molecular changes occurring in canine demodicosis using mass spectrometry and pathway enrichment analysis. The results indicate that endoplasmic reticulum stress promotes canine demodicosis through regulation of three linked signalling pathways: eIF2, mTOR, and eIF4 and p70S6K. These pathways are involved in the modulation of Toll-like receptors, most notably TLR2, and have been shown to play a role in the pathogenesis of skin diseases in both dogs and humans. Moreover, these pathways are also implicated in the promotion of immunosuppressive M2 phenotype macrophages. Immunohistochemical analysis, utilising common markers of dendritic cells and macrophages, verified the presence of M2 macrophages in canine demodicosis. The proteomic analysis also identified immunological disease, organismal injury and abnormalities and inflammatory response as the most significant underlying diseases and disorders associated with canine demodicosis. This study demonstrates that Demodex mites, through ER stress, unfolded protein response and M2 macrophages contribute to an immunosuppressive microenvironment, thereby assisting in their proliferation.

Integrating Single-Cell and Spatial Transcriptomics Reveals Heterogeneity of Early Pig Skin Development and a Subpopulation with Hair Placode Formation.

The dermis and epidermis, crucial structural layers of the skin, encompass appendages, hair follicles (HFs), and intricate cellular heterogeneity. However, an integrated spatiotemporal transcriptomic atlas of embryonic skin has not yet been described and would be invaluable for studying skin-related diseases in humans. Here, single-cell and spatial transcriptomic analyses are performed on skin samples of normal and hairless fetal pigs across four developmental periods. The cross-species comparison of skin cells illustrated that the pig epidermis is more representative of the human epidermis than mice epidermis. Moreover, Phenome-wide association study analysis revealed that the conserved genes between pigs and humans are strongly associated with human skin-related diseases. In the epidermis, two lineage differentiation trajectories describe hair follicle (HF) morphogenesis and epidermal development. By comparing normal and hairless fetal pigs, it is found that the hair placode (Pc), the most characteristic initial structure in HFs, arises from progenitor-like OGN+/UCHL1+ cells. These progenitors appear earlier in development than the previously described early Pc cells and exhibit abnormal proliferation and migration during differentiation in hairless pigs. The study provides a valuable resource for in-depth insights into HF development, which may serve as a key reference atlas for studying human skin disease etiology using porcine models.

Lymphatic-Dependent Modulation of the Sensitization and Elicitation Phases of Contact Hypersensitivity

Allergic contact dermatitis is a common inflammatory skin disease comprising 2 phases. During sensitization, immune cells are activated by exposure to various allergens, whereas repeated antigen exposure induces local inflammation during elicitation. In this study, we utilized mouse models lacking lymphatics in different skin regions to characterize the role of lymphatics separately in the 2 phases, using contact hypersensitivity as a model of human allergic inflammatory skin diseases. Lymphatic-deficient mice exhibited no major difference to single antigen exposure compared to controls. However, mice lacking lymphatics in both phases displayed reduced inflammation after repeated antigen exposure. Similarly, diminished immune response was observed in mice lacking lymphatics only in sensitization, whereas the absence of lymphatics only in the elicitation phase resulted in a more pronounced inflammatory immune response. This exaggerated inflammation is driven by neutrophils impacting regulatory T cell number. Collectively, our results demonstrate that skin lymphatics play an important but distinct role in the 2 phases of contact hypersensitivity. During sensitization, lymphatics contribute to the development of the antigen-specific immunization, whereas in elicitation, they moderate the inflammatory response and leukocyte infiltration in a neutrophil-dependent manner. These findings underscore the need for novel therapeutic strategies targeting the lymphatics in the context of allergic skin diseases.

Functional human skin explants as tools for assessing mast cell activation and inhibition.

Mast cells are activated through a variety of different receptors to release preformed granules and mediators synthesized de novo. However, the physiology and function of mast cells are not fully understood. Traditional studies of mast cell activation in humans have utilized cultures of tissue-derived mast cells including CD34+ progenitor cells or well-characterized commercially available cell lines. One limitation of these methods is that mast cells are no longer in a natural state. Therefore, their applicability to human skin disorders may be limited. Human skin explant models have been utilized to investigate the short-term effects of cell mediators, drugs, and irritants on skin while avoiding the ethical concerns surrounding in vivo stimulation studies with non-approved agents. Nonetheless, few studies have utilized intact human tissue to study mast cell degranulation. This "Methods" paper describes the development and application of an intact skin explant model to study human mast cell activation. In this manuscript, we share our protocol for setting up ex vivo human skin explants and describe the results of stimulation experiments and techniques to minimize trauma-induced histamine release. Skin explants were generated using de-identified, full-thickness, non-diseased skin specimens from plastic and reconstructive surgeries. Results were reproducible and demonstrated FcɛRI- and MRGPRX2-induced mediator release which was inhibited with the use of a BTK inhibitor and QWF, respectively. Thus, this explant model provides a quick and accessible method of assessing human skin mast cell activation and inhibition.

The Past, Present, Future: Pathophysiology, Diagnosis, and Treatment of Human Skin Diseases

When thinking of skin disease, cancer comes up almost immediately as an example. While the American Cancer Society lists 6 major cancer types, the National Institute of Arthritis and Musculoskeletal and Skin Diseases identifies 13 significant benign skin disorders, reflecting the diversity of skin conditions in dermatology. This topical review aims to provide an overview of the pathophysiology of these major skin cancers and disorders and to summarize conventional diagnostic methods and current treatment approaches.

Canine Atopic Dermatitis: Prevalence, Impact, and Management Strategies.

Atopic dermatitis (AD) is a common inflammatory and pruritic allergic skin disease in humans and dogs worldwide. The pathogenesis of AD is multifactorial, immunologically complex, and may involve genetic factors, epidermal barrier dysfunction, microbiome changes, immune dysregulation, and allergic sensitization. Across species, prevalence of AD is on the rise. At present, there is no cure for canine AD (CAD). The treatment for CAD is multifaceted and aimed at controlling the pruritus, associated inflammation, and infections, repairing the skin barrier function, and dietary management. This review presents data on prevalence, impact, and complex immunological interactions in AD with a focus on subsequent management of the disease in the canine population. A multimodal approach for management of CAD to address varying clinical signs and responses to therapies is discussed.

Rodent models of dermatological disorders.

To assess the possible beneficial effects of drugs and drug candidates, different dermatological disease models are available in rodents. These models are able to mimic one or more characteristic features of the disorders, but not completely recapitulate the pathogenesis of the human skin diseases. Therefore, to improve the technology many new models have been developed both by genetic engineering and by chemical or physical induction. Currently the in vivo rodent models provide the physiologically most relevant approach to produce the pathology related to the majority of dermatological diseases. In this short review some widely used animal techniques (psoriasis, allergic contact dermatitis, atopic dermatitis, wound healing, melanoma and non-melanoma type skin cancers and UV erythema) are shown which are currently applied in pharmacological, pharmacokinetic, pharmaceutical and dermatological research. First the main points of the human pathomechanism are shown and afterwards the rodent models are briefly discussed. Finally critical evaluation is provided by the authors. However, according to the 3R rule the number of experimental animals is strongly suggested to be reduced, therefore the advanced in vitro and ex vivo techniques become more and more important contrary to in vivo preclinical methods also in dermatological research. As it is described in the outlook section, although the 2D/3D in vitro and skin on-a-chip techniques are promising and have many advantages they are not able to completely substitute the animal models in their vascular, immunological, secretory and neural complexity.

WB518, a novel STAT3 inhibitor, effectively alleviates IMQ and TPA-induced animal psoriasis by inhibiting STAT3 phosphorylation and Keratin 17

ObjectivesPsoriasis is a prevalent chronic inflammatory skin disease in humans that is characterized by frequent relapses and challenging to cure. WB518 is a novel small molecule compound with an undisclosed structure. Therefore, our study aimed to investigate the therapeutic potential of WB518 in vitro and in vivo for the treatment of psoriasis, specifically targeting the abnormal proliferation, aberrant differentiation of epidermal keratinocytes, and pathogenic inflammatory response. Materials and MethodsWe employed dual luciferase reporter assay to screen compounds capable of inhibiting STAT3 gene transcription. Flow cytometry was utilized to analyze CD3-positive cells. Protein and mRNA levels were assessed through Western blotting, immunofluorescence, immunohistochemistry, and real-time PCR. Cell viability was measured using the MTS assay, while in vivo models of psoriasis induced by IMQ and TPA were employed to study the anti-psoriasis effect of WB518. ResultsWB518 was found to significantly reduce the mRNA and protein levels of Keratin 17 (K17) in HaCaT cells by inhibiting the phosphorylation of STAT3 Tyr705 (Y705). In the IMQ and TPA-induced psoriasis mouse model, WB518 effectively improved scaling, epidermal hyperplasia, and inflammation. WB518 also suppressed the expression of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-17, and IL-23. Furthermore, WB518 decreased the proportion of CD3-positive cells in the psoriatic skin of mice. ConclusionsWB518 exhibits promising potential as a treatment candidate for psoriasis.

Computer vision model for the detection of canine pododermatitis and neoplasia of the paw.

Artificial intelligence (AI) has been used successfully in human dermatology. AI utilises convolutional neural networks (CNN) to accomplish tasks such as image classification, object detection and segmentation, facilitating early diagnosis. Computer vision (CV), a field of AI, has shown great results in detecting signs of human skin diseases. Canine paw skin diseases are a common problem in general veterinary practice, and computer vision tools could facilitate the detection and monitoring of disease processes. Currently, no such tool is available in veterinary dermatology. Digital images of paws from healthy dogs and paws with pododermatitis or neoplasia were used. We tested the novel object detection model Pawgnosis, a Tiny YOLOv4 image analysis model deployed on a microcomputer with a camera for the rapid detection of canine pododermatitis and neoplasia. The prediction performance metrics used to evaluate the models included mean average precision (mAP), precision, recall, average precision (AP) for accuracy and frames per second (FPS) for speed. A large dataset labelled by a single individual (Dataset A) used to train a Tiny YOLOv4 model provided the best results with a mean mAP of 0.95, precision of 0.86, recall of 0.93 and 20 FPS. This novel object detection model has the potential for application in the field of veterinary dermatology.

Development of Physiologically Relevant Skin Organoids from Human Induced Pluripotent Stem Cells.

The development of skin organs for studying developmental pathways, modeling diseases, or regenerative medicine purposes is a major endeavor in the field. Human induced pluripotent stem cells (hiPSCs) are successfully used to deriveskin cells, but the field is still far from meeting the goal of creating skin containing appendages, such as hair follicles and sweat glands. Here, the goal is to generate skin organoids (SKOs) from human skin fibroblast or placental CD34+ cell-derived hiPSCs. With all three hiPSC lines, complex SKOs with stratified skin layers and pigmented hair follicles are generated with different efficacies. In addition, the hiPSC-derived SKOs develop sebaceous glands, touch-receptive Merkel cells, and more importantly eccrine sweat glands. Together, physiologically relevant skin organoids are developed by direct induction of embryoid body formation, along with simultaneous inactivation of transforming growth factor beta signaling, activation of fibroblast growth factor signaling, and inhibition of bone morphogenetic protein signaling pathways. The skin organoids created in this study can be used as valuable platforms for further research into human skin development, disease modeling, or reconstructive surgeries.